1. Field of the Invention
This invention relates to pharmaceutical compounds and to compositions containing them, being primarily concerned with substances of use as anti-ischaemic agents.
2. Description of the Prior Art
Free radicals are reactive substances produced constantly in the body during respiration, tissue turnover, tissue repair and in combatting infections. Under normal conditions, the antioxidant defence mechanisms operational in the body are able to minimise biological damage. However, there are situations, e.g. in certain disease processes, when free radical production overwhelms the natural defence mechanisms.
A substantial amount of evidence has been accumulated which suggests that oxygen free radicals mediate ischaemia-reperfusion injury in a variety of tissues, including the heart, lung, kidney, gastrointestinal tract, brain and inflammatory joint disease such as rheumatoid arthritis (Korthius and Granger, 1986, in `Physiology of Oxygen Radicals` Eds. Taylor, Matalos and Ward; Allen et al., 1989, Lancet ii, 282-283). Both direct and spin trapping EPR techniques have demonstrated that a burst of oxygen free radical production occurs after reperfusion of ischaemic tissue (Blasig et al., 1986 Stud. Biophys. 116, 35-42; Arroyo et al., 1987 FEBS Lett. 221 101-104; Zweier et al., 1987 PNAS USA 84, 1404-1407; Allen et al., 1989, Lancet ii, 282-283). Ischaemia-reperfusion injury is thought to involve a multicomponent process with a burst of free radical production occurring following reperfusion and a second event, possibly inflammatory damage, occurring later. Based on the protective effects of intravascularly administered selective enzyme inhibitors and radical scavenging agents/enzymes, it is widely believed that xanthine oxidase associated with endothelial cells is probably the main source for the production of oxygen radicals responsible for inducing tissue damage during the reperfusion phase.
Treatment of ischaemia/reperfusion induced injury requires the development of compounds which suppress the harmful effects of oxygen radicals during both the reperfusion and inflammatory phases. An obvious approach would be the administration of agents that selectively block currently known pathways of radical generation and the release of inflammatory mediators. For example, peroxynitrite, formed by the reaction of nitric oxide and superoxide is thought to be one of the species responsible for bringing about the toxicity of the oxygen free radicals but inhibition of nitric oxide production may be deleterious because of its physiological role in regulating thrombogenicity and vasodilation. A more suitable target would be the inhibition of superoxide production. The above is a particularly attractive strategy, due to the possibility of selectively inhibiting xanthine oxidase, the enzyme involved in the first (reperfusion) stage of ischaemic injury.
Due to the multifactorial nature of ischaemia induced injury, in addition to xanthine oxidase inhibitory activity, compounds with potent anti-oxidant activity are required to minimise free radical mediated damage to biological molecules during both the reperfusion and inflammatory phases in disease states wherein these symptoms manifest themselves. Finally compounds which bind redox active metals such as iron with high affinity such that the metal complex is not able to take part in redox cycling reactions will provide additional benefit.
It has been a problem to find compounds which fulfil some or all these requirements.